KEAP1 E3 Ligase-Mediated Downregulation of NF-κB Signaling by Targeting IKKβ

Lee, Dung‐Fang; Kuo, Hsu Ping; Liu, Mo; Chou, Chao-Kai; Xia, Weiya; Du, Yi; Shen, Jia; Chen, Chun‐Te; Huo, Longfei; Hsu, Ming Chuan; Li, Chia Wei; Ding, Qingqing; Liao, Tsai Lien; Lai, Chien‐Chen; Lin, Ann Chi; Chang, Ya Hui; Tsai, Shih Feng; Li, Long-yuan; Hung, Mien‐Chie

doi:10.1016/j.molcel.2009.07.025

Cited by 346 publications

(288 citation statements)

References 21 publications

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“…BARD analogues promote activation of Nrf2 via covalent modification of the specific thiols in the Keap1 molecules [26]. In addition to repression of Nrf2, Keap1 participates in repression of IKKB (the positive regulator of NF-k B) by facilitating its proteasomal degradation [55]. Accordingly oxidative or covalent modification of Keap1 can lead to release of IKKB, phosphorylation of IKB (the NF k B inhibitor) by IKKB, dissociation of IKB-NF k B complex, and nuclear translocation of NF k B, events that trigger transcriptional upregulation of pro-inflammatory and pro-fibrotic mediators.…”

Section: Discussionmentioning

confidence: 99%

Dose-dependent deleterious and salutary actions of the Nrf2 inducer dh404 in chronic kidney disease

Vaziri¹,

Liu²,

Farzaneh³

et al. 2015

Free Radical Biology and Medicine

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Oxidative stress and inflammation play a central role in progression and complications of CKD and are, in part, due to impairment of the Nrf2 system which regulates expression of antioxidant and detoxifying molecules. Natural Nrf2 inducing phytochemicals have been shown to ameliorate kidney disease in experimental animals. However due to adverse outcomes clinical trial of synthetic Nrf2 activator, bardoxolone methyl (BARD), in CKD patients was terminated. BARD activates Nrf2 via 2 covalent modification of reactive cysteine residues in Nrf2 repressor molecule, Keap-1. In addition to Nrf2, Keap1 suppresses IKKB, the positive regulator of NF k B. Treatment with BARD analog, dh404, at 5-20 mg/kg/day in diabetic obese Zucker rats exacerbates whereas its use at 2 mg/kg/day in 5/6 nephrectomized rats attenuates CKD progression. We, therefore, hypothesized that deleterious effects of high dose BARD are mediated by activation of NF k B.CKD (5/6 nephrectomized) rats were randomized to receive dh404 (2 or 10mg/kg/day) or vehicle for 12 weeks. Vehicle-treated group exhibited glomerulosclerosis, interstitial fibrosis and inflammation, activation of NF k B, upregulation of oxidative, inflammatory and fibrotic pathways, and suppression of Nrf2 activity and its key target gene products. Treatment with low dose dh404 restored Nrf2 activity and expression of its target genes, attenuated activation of NF k B and fibrotic pathways, and reduced glomerulosclerosis, interstitial fibrosis and inflammation. In contrast treatment with high dh404 dosage intensified proteinuria, renal dysfunction and histological abnormalities, amplified up-regulations of NF k B and fibrotic pathways, and suppression of Nrf2 system. Thus therapy with BARD analogs exerts a dose-dependent dimorphic impact on CKD progression.

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Section: Discussionmentioning

confidence: 99%

Dose-dependent deleterious and salutary actions of the Nrf2 inducer dh404 in chronic kidney disease

Vaziri¹,

Liu²,

Farzaneh³

et al. 2015

Free Radical Biology and Medicine

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“…Thus, these cysteine residues are candidate sites for thiocarbamoylation by ITCs, although direct evidence for covalent binding to NF-B subunits by this class of molecule is lacking. Very recent studies have demonstrated that, in addition to Nrf2, Keap1 can function as a ubiquitin E3 ligase for IKK and thereby downregulate NF-B activity [55]. However, it is not known whether modulation of Keap1 by ITCs per se leads to increased expression/activity of IKK.…”

Section: Hif-independent Control Of Angiogenesismentioning

confidence: 99%

Anti-angiogenic effects of dietary isothiocyanates: Mechanisms of action and implications for human health

Cavell

Alwi

Donlevy

et al. 2011

Biochemical Pharmacology

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To cite this version:Breeze E. Cavell, Sharifah S. Syed Alwi, Alison Donlevy, Graham Packham. Anti-angiogenic effects of dietary isothiocyanates; mechanisms of action and implications for human health. Biochemical Pharmacology, Elsevier, 2010, 81 (3) This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. A c c e p t e d M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 Isothiocyanates and angiogenesis -3 - AbstractIsothiocyanates (ITCs) are electrophilic compounds derived from plants and are thought to play a major role in the potential chemopreventive effects associated with high intake of cruciferous vegetables. ITCs are also being evaluated for chemotherapeutic activity in early phase clinical trials. In addition to their effects on carcinogen metabolism and cancer cell survival and proliferation, ITCs have been shown to effectively interfere with angiogenesis in vitro and in vivo. Angiogenesis is the development of a new blood supply from existing vasculature and is required for tumours to develop beyond a small size limit determined by the diffusion limit for oxygen. Inhibition of angiogenesis may play a key role in the potential chemopreventive/chemotherapeutic activity of ITCs. In this review we highlight recent data demonstrating that ITCs have anti-angiogenic activity and identify potential molecular targets for these effects, including hypoxia-inducible factor (HIF), nuclear factor B (NF-B), activator protein 1 (AP1) and tubulin. We also discuss these findings in light of the potential chemopreventive/chemotherapeutic effects of ITCs.

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“…One of the Keap1 substrates for ubiquitination is Ikkβ which upregulates the Nf-κB transcription factor through the negative regulation of its inhibitor Ikbα. 9 Under oxidative stress, Ikkβ is released from Keap1, and mediates the activation of Nf-kB regulated genes, resulting in increased growth, proliferation and anti-apoptosis, thus contributing to cell survival and tumor progression. 10 Moreover, recent studies suggest that under oxidative stress conditions Keap1 modulates the intrinsic apoptotic pathway through the degradation of Bcl2 and Bcl-xL antiapoptotic proteins.…”

Section: Introductionmentioning

confidence: 99%

AberrantKeap1methylation in breast cancer and association with clinicopathological features

et al. 2013

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KEAP1 E3 Ligase-Mediated Downregulation of NF-κB Signaling by Targeting IKKβ

Cited by 346 publications

References 21 publications

Dose-dependent deleterious and salutary actions of the Nrf2 inducer dh404 in chronic kidney disease

Dose-dependent deleterious and salutary actions of the Nrf2 inducer dh404 in chronic kidney disease

Anti-angiogenic effects of dietary isothiocyanates: Mechanisms of action and implications for human health

AberrantKeap1methylation in breast cancer and association with clinicopathological features

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